Stroke prevention in AF patients: SOC versus NOAC

Stroke prevention in AF patients: SOC versus NOAC Prof. Dr. Andreas Zirlik Cardio Luxor 2015 Disclosures for Andreas Zirlik, MD In compliance with CME policy, the following disclosures to the session audience are declared: Research support/p.i. Travel support Astellas, Astra Zeneca, ResMed, Novartis, Medtronic Daichi Sankyo, Astellas, Lilly, Medtronic, Pfizer, Sanofi Aventis, Novartis, Bayer Health Care Consultant Bayer, Boehringer Ingelheim, Rigel, Cardiorentis, Medscape Major stockholder Honoraria for lectures No relevant conflicts of interest to declare Bayer Health Care, Astra Zeneca, Medtronic, ResMed, Boehringer Ingelheim, Rigel, Sanofi Aventis, Pfizer, Janssen- Cilag 1

New anticoagulants: Practical issues to be discussed Background, Pharmacology, and Platform of evidence for NOACs ESC Guideline Update 2012 Case Presentations Practical Issues to be discussed Dosing Switching Monitoring vs. Measuring Bleeding Elective Surgery Triple Therapy (DAPT+OAC) EHRA Guide Ongoing Studies Conclusion: Individualized therapeutic approach Untreated atrial fibrillation bears considerable risk of stroke Death 25% Invalid 35% Pers. Deficit 35% No deficit 5% Flegel KM et al., J Clin Epidemiol 1991 2

Placebo Warfarin ASS Warfarin ASS + Clopidogrel Warfarin 1/19/2015 Efficacy of dose-adjusted VKA Relative risk reduction thrombembolic events 10 9 62% 8 7 36% 6 5 ~30% 4 3 2 1 0 Warfarin Warfarin Warfarin Lip et al. 2002 Lip et al. 2002 The ACTIVE writing group, 2006 Modified Lip GYH et al. BMJ 2002; 325:1022 1025 and The ACTIVE Writing Group Lancet 2006; 367: 1903 1912. Anticoagulation with Vitamin K antagonists has many disadvantages ACC/AHA/ESC Guidelines, Eur Heart J 2006 3

GARFIELD: OAC is underused in clinical practice Kakkar AK et al. PlosOne 2013; 8(5): e63479 New anticoagulants: Summary of pharmacology Apixaban Rivaroxaban Dabigatran Target enzyme Factor Xa Factor Xa Thrombin Bioavailability (%) 60 90 6 Prodrug No No Yes T max (median, h) 3 2.5 1.5 t 1/2 (h) 8 15 7 11 14 17 Renal elimination (%) 25 33 (in active form) 80 Adapted from Mavrakanas T, Bounameaux H. Pharmacol Ther 2011;130:46 58. 4

S T R O K E P R E V E N T I O N RE-LY: Dabigatran vs. Warfarin Pat. with AF and 1 RF, Randomization Dabigatran 2x110mg/d vs. Dabigatran 2x150mg/d vs. Warfarin, n=18113 1 EP: stroke or systemic embolism Efficacy Safety Non-inferiority p=0.001 Superiority p=0.34 Non-inferiority p=0.001 Superiority p=0.001 NEJM 2009; 361:1139-1151 Revised Data NEJM 2010; 363:1875-1876 5

RELY: Safety NEJM 2009; 361:1139-1151 Revised Data NEJM 2010; 363:1875-1876 S T R O K E P R E V E N T I O N ROCKET: Rivaroxaban vs. Warfarin Pat. with AF and 2 RF, Randomization Rivaroxaban 1x20mg/d vs. Warfarin, n=14264 1 EP: stroke or systemic embolism Efficacy Safety Non-inferiority p=0.001 Superiority on per protocol analysis * * * 6

S T R O K E P R E V E N T I O N ARISTOTLE: Apixaban vs. Warfarin Pat. with AF and 1 RF, Randomization Apixaban 2x5mg/d vs. Warfarin, n=18201 1 EP: stroke or systemic embolism Efficacy Safety Superiority p=0.001 Superiority p=0.001 Stroke or systemic embolism Major Bleeding 7

New anticoagulants: Practical issues to be discussed Background, Pharmacology, and Platform of evidence for NOACs ESC Guideline Update 2012 Case Presentations Practical Issues to be discussed Dosing Switching Monitoring vs. Measuring Bleeding Elective Surgery Triple Therapy (DAPT+OAC) EHRA Guide Ongoing Studies Conclusion: Individualized therapeutic approach ESC Guidelines 2012 8

New anticoagulants: Practical issues to be discussed Background, Pharmacology, and Platform of evidence for NOACs ESC Guideline Update 2012 Case Presentations Practical Issues to be discussed Dosing Switching Monitoring vs. Measuring Bleeding Elective Surgery Triple Therapy (DAPT+OAC) EHRA Guide Ongoing Studies Conclusion: Individualized therapeutic approach 9

Case 1 A 78-year-old woman with new onset AF CVRF: coronary 2-vessel disease, acute MI two years ago, arterial hypertension Cr-Clearance around 40ml/min Otherwise good health condition On Enoxaparin s.c. therapeutically since two days Question to the audience: Does our patient need long-term therapeutic anticoagulation? 1 Yes 2 No 10

How to assess risk of stroke? 0 = low: no AC 1 therapeutic AC How to assess risk of bleeding? 11

Question to the audience: What would be your agent of choice? 1 Warfarin 2 Dabigatran 2 Rivaroxaban 3 Aspirin Case 1 A 78-year-old woman with new onset AF CVRF: coronary 2-vessel disease, acute MI two years ago, arterial hypertension Cr-Clearance around 40ml/min Otherwise good health condition On Enoxaparin s.c. therapeutically since two days 12

RELY: Age, renal function Safety Rate (% per year) D 110 W D 110 mg vs. W p = (for interaction) Age < 65 Age 65-74 Age 75 0.76 2.12 4.21 2.32 3.08 4.09 CrCl 30-50 CrCl 51-80 CrCl > 80 5,07 2,62 1,36 5,17 3,44 2,18 Healey JS et al. J Am Coll Cardiol 2010; 55: A4 Healey JS. Poster presentation at ACC, Orlando, Mar 14th 2010 Hijazi Z et al., Circulation 9 Dec 2013 Epub bevor print 0,50 1,00 1,50 Dabigatranetexilat better Warfarin better ROCKET: impaired renal function Safety 13

Uchino and Hernandez. Arch Int Med 2012;172:397 Meta-analysis and trial sequential analysis of RCTs: Rivaroxaban treated subjects have reduced risk for myocardial infarction Results 1 Study or Subgroup ATLAS ACS 2 TIMI 51 ATLAS ACS TIMI 46 Rivaroxaban Comparator Odds Ratio M-H, Random Events Total Events Total Weight (95% CI) 384 10.229 229 5113 61.2 % 0.83 (0.70-0.98) 67 2331 44 1160 11.4% 0.75 (0.51-1.11) Odds Ratio M-H, Random, 95%CI RECORD 1 7 2290 6 2224 1.4% 1.18 (0.39-3.50) RECORD 2 4 1228 3 1229 0.8% 1.34 (0.30-5.98) RECORD 3 1 1220 2 1239 0.3% 0.51 (0.05-5.60) RECORD 4 1 1584 5 1564 0.4% 0.20 (0.02-1.69) ROCKET AF 101 7111 126 7125 24.6% 0.80 (0.61-1.04 Total 25912 19654 100% 0.82 (0.72-0.93) Total events 565 415 Heterogeneity: Tau²=0.00; Chi²=2.93; df=6 (p=0.82; I²=0% Test for overall effect: Z=3.05 (p=0.02) 0.2 0.5 1 2 5 Rivaroxaban better Comparator better Chatterjee S et al. presented at AHA 2012 14

Question to the audience: What would be the recommended dose of Rivaroxaban for our patient? 1 2 x 15mg 2 1 x 15mg 2 1 x 20mg 3 2 x 2.5mg Dosing of new oral anticoagulants for stroke prevention in atrial fibrillation Anticoagulant Dabigatran etexilate Rivaroxaban Apixaban Dosing for stroke prevention in atrial fibrillation 2x150mg >80years or 75-80 with high bleeding risk: 2x110mg CrCl 30-49 and high bleeding risk: 2x110mg CrCl <30: contraindication 1x20mg CrCl 15 49: 1x15mg CrCl <15: contraindication 2x5mg CrCl 15-49: 2x2.5mg CrCl <15: contraindication 15

Adherent patients (%) Bleeding incidence (%) Adherent patients (%) Ratio (edoxaban/warfarin) 1/19/2015 od drugs within a polydrug regimen show better adherence than bid drugs 10,697 patients with AF initiated on diabetes and hypertension drugs: 45% already taking 2 different drugs at baseline (US: 2004 2009) 80 78 76 74 72 70 68 66 64 62 60 Overall adherence # MPR 0.8 * Total population *p<0.001 vs bid; # Mean exposure: 447 days od, 406 days bid; p=0.017 vs bid Laliberté et al, Adv Ther 2012;29:675 690 Age 65 years 80 75 70 65 60 55 50 45 40 * Adherent patients over time PDC 0.8 * od bid 3 6 12 18 Months since therapy initiation * * Edoxaban phase II data support the selection of od dosing in AF: higher bleeding rates in bid correlated with higher C trough Total daily dose 30 mg Total daily dose 60 mg Total daily dose 120 mg 20 2.15* 2.5 15 2.0 1.49* 1.5 10 5 0.63 0.92 1.00 1.0 0.5 0 13/235 19/234 32/244 34/180 22/250 Edoxaban 30 mg od Edoxaban 60 mg od Edoxaban 30 mg bid Edoxaban 60 mg bid Warfarin N=1146 patients with AF *p<0.03 vs warfarin 1. Salazar et al. Thromb Haemost 2012;107:925 936; 2. Weitz et al. Thromb Haemost 2010;104:633 641 16

New anticoagulants: Practical issues to be discussed Background, Pharmacology, and Platform of evidence for NOACs ESC Guideline Update 2012 Case Presentations Practical Issues to be discussed Dosing Switching Monitoring vs. Measuring Bleeding Elective Surgery Triple Therapy (DAPT+OAC) EHRA Guide Ongoing Studies Conclusion: Individualized therapeutic approach Question to the audience: How to switch in our case from enoxaparin bid. to Rivaroxaban 1 simultaneous dosing 2 6h after last dose of enoxaparin 2 12h after last dose of enoxaparin 3 24h after last dose of enoxaparin 17

Anti-Factor Xa activity (change from baseline; ng/ml enoxaparin) 1/19/2015 New anticoagulants: Switching strategies VKA to NOAC Parenteral anticoagulant to NOAC: Intravenous unfractioned heparin (UFH) Low molecular weight heparin (LMWH) INR <2.0: immediate INR 2.0 2.5: immediate or next day INR >2.5: use INR and VKA half-life to estimate time to INR <2.5 Start once UFH discontinued (t½=2h). May be longer in patients with renal impairment Start when next dose would have been given NOAC to VKA Administer concomitantly until INR in appropriate range Measure INR just before next intake of NOAC Re-test 24h after last dose of NOAC Monitor INR in first month until stable values (2.0 3.0) achieved NOAC to parenteral anticoagulant NOAC to NOAC Initiate when next dose of NOAC is due Initiate when next dose is due except where higher plasma concentrations expected (e.g. renal impairment) Aspirin or clodiprogel to NOAC Switch immediately, unless combination therapy needed Heidbuchl et al. EP Europace 15: 625-651 (2013) Evidence for od dosing: similar onset of action to enoxaparin 4 Enoxaparin 40 mg Rivaroxaban 10 mg 3 2 1 0 0 4 8 12 16 20 24 28 32 36 40 44 48 Time (hours) Note: This was one of the early observations that suggested that od might be feasible Kubitza et al. J Thromb Haemost 2005;3(Suppl.1):P1704 18

New anticoagulants: Practical issues to be discussed Background, Pharmacology, and Platform of evidence for NOACs ESC Guideline Update 2012 Case Presentations Practical Issues to be discussed Dosing Switching Monitoring vs. Measuring Bleeding Elective Surgery Triple Therapy (DAPT+OAC) EHRA Guide Ongoing Studies Conclusion: Individualized therapeutic approach Case 3 A 48-year-old man has been treated for 2 months with warfarin for AF No bleeding problems; INR regulation is average General health is excellent He will be travelling in rural India for the next 4 months with little access to medical facilities and only intermittent facilities for international communication 19

Question to the audience: How should Rivaroxaban treatment be monitored? 1 INR should be tested every month 2 PTT should be tested every month 2 anti-xa should be tested every month 3 None of the above Measuring NOACs - If you seek to measure drug activity in cases of overdosing or bleeding: - Anti Xa chromogenic assay for Rivaroxaban - Anti IIa chromogenic assay or dtt for Dabigatran - In our experience rarely necessary - INR, PTT, and other coagulation tests will be altered but are not clinically meaningful 20

New anticoagulants: Practical issues to be discussed Background, Pharmacology, and Platform of evidence for NOACs ESC Guideline Update 2012 Case Presentations Practical Issues to be discussed Dosing Switching Monitoring vs. Measuring Bleeding Elective Surgery Triple Therapy (DAPT+OAC) EHRA Guide Ongoing Studies Conclusion: Individualized therapeutic approach Case 4 A 60-year-old man taking Rivaroxaban 1x20mg/d for AF since 2 months Presents in the ER with acute symptomatic gastric bleeding Drop in Hemoglobin by 5 points 21

ESC Guidelines 2012 New anticoagulants: Practical issues to be discussed Background, Pharmacology, and Platform of evidence for NOACs ESC Guideline Update 2012 Case Presentations Practical Issues to be discussed Dosing Switching Monitoring vs. Measuring Bleeding Elective Surgery Triple Therapy (DAPT+OAC) EHRA Guide Ongoing Studies Conclusion: Individualized therapeutic approach 22

Case 6 77-year-old female with AF, treated rivaroxaban 1x20 mg/d Must undergo urgent cholecystectomy No prior bleeding problems; New anticoagulants: elective surgery Before surgery After surgery Dabigatran CrCl>80: 24h (high risk 2d) 50-80: 1-2d (high risk 2-3d) 30-50: 2-3d (high risk 4d) as soon as possible Rivaroxaban at least 24h as soon as possible 23

New anticoagulants: Practical issues to be discussed Background, Pharmacology, and Platform of evidence for NOACs ESC Guideline Update 2012 Case Presentations Practical Issues to be discussed Dosing Switching Monitoring vs. Measuring Bleeding Elective Surgery Triple Therapy (DAPT+OAC) EHRA Guide Ongoing Studies Conclusion: Individualized therapeutic approach Case 7 82-y/o female with posterior MI CVRF: Hypertension, Diabetes ND: chron. OAC with Warfarin for Afib Cath: 2-VD, Occlusion RCA, medial 90% LAD-Stenosis Th.: PCI/DES RCA acutely and PCI/DES LAD Seite 49 24

Patents with ACS and DE-Stent The Freiburg Regimen PPI ASS Clopidogrel VKA INR 2,0-2,5 INR 2-3 1 Month 1 Year ACS/ DE-Stent Eur Heart J. 2014 Jan;35(4):216-23. Patents with ACS and DE-Stent The Freiburg Regimen PPI ASS Clopidogrel Riva 10mg Riva 15mg Riva 20mg 1 Month 1 Year ACS/ DE-Stent 25

New anticoagulants: Practical issues to be discussed Background, Pharmacology, and Platform of evidence for NOACs ESC Guideline Update 2012 Case Presentations Practical Issues to be discussed Dosing Switching Monitoring vs. Measuring Bleeding Elective Surgery Triple Therapy (DAPT+OAC) EHRA Guide Ongoing Studies Conclusion: Individualized therapeutic approach EHRA practical guide on the use of new oral anticoagulants in patients with nonvalvular atrial fibrillation Hein Heidbuchel 1, M.D., Ph.D., Peter Verhamme 1, M.D., Ph.D., Marco Alings 2, M.D., Ph.D., Matthias Antz 3, M.D., Werner Hacke 4, M.D., Jonas Oldgren 5, M.D., Ph.D., Peter Sinnaeve 1, M.D., Ph.D., A. John Camm 6, M.D., Paulus Kirchhof 7, M.D., Ph.D. 1. Department of Cardiovascular Medicine, University Hospital Gasthuisberg, University of Leuven, Leuven, Belgium; 2. Department of Cardiology, Amphia Ziekenhuis, Breda, Netherlands; 3. Department of Cardiology, Klinikum Oldenburg, Oldenburg, Germany; 4. Department of Neurology, Ruprecht Karls Universität, Heidelberg, Germany; 5. Uppsala Clinical Research Center and Dept of Medical Sciences, Uppsala University, Uppsala, Sweden; 6. Clinical Cardiology, St George s University, London, United Kingdom; 7. University of Birmingham Centre for Cardiovascular Sciences, Birmingham, UK, and Department of Cardiology and Angiology, University of Münster, Germany 26

New anticoagulants: Practical issues to be discussed Background, Pharmacology, and Platform of evidence for NOACs ESC Guideline Update 2012 Case Presentations Practical Issues to be discussed Dosing Switching Monitoring vs. Measuring Bleeding Elective Surgery Triple Therapy (DAPT+OAC) EHRA Guide Ongoing Studies Conclusion: Individualized therapeutic approach Take home messages: NOACs are superior to Warfarin in terms of efficacy and safety. Direct comparison between the trials and particularly between subgroups is unsound given the differences in design and collective. The question which drug for which patient should be based on trial data and basic pharmacology. Factor Xa inhibitors such as rivaroxaban are more suited for the elderly and renally impaired than DTIs. Rivaroxaban affords the added advantage of a single dosing, broad spectrum of indications, and excellent data in CV comorbidity. 27

What is the bleeding risk under triple therapy? Paikin et al. Circulation 2010;121;2067-2070 28

Cumulative incidence of bleeding 1/19/2015 Consensus Statement triple therapy 2010 Thromb Haemost 2010; 103: 13 28 The WOEST Trial: First randomised trial comparing two regimens with and without aspirin in patients on oral anticoagulant therapy undergoing coronary stenting 50 % 40 % 30 % 20 % 10 % 0 % 0 30 60 90 120 180 270 365 Days n at risk: 284 210 194 186 181 173 159 140 279 253 244 241 241 236 226 208 29

WOEST 9 8 7 p=0.027 6.4 Secondary Endpoint p=0.876 7.3 6.8 Lancet 2013:381:1107-1115 Double therapy group 6 5 p=0.382 4.7 Triple therapy group 4 3 2.6 3.3 p=0.128 2.9 p=0.165 3.2 2 1 1.1 1.5 0 Death MI TVR Stroke ST MI=any myocardial infarction; TVR= target vessel revascularisation (PCI + CABG); ST= stent thrombosis 30

XARELTO (rivaroxaban) Use in Patients With AF Undergoing PCI: PIONEER AF-PCI 2100 patients with NVAF No prior stroke/tia PCI with stent placement 72 hours After Sheath removal R A N D O M I Z E 1,6, or 12 months XARELTO 2.5 mg bid Clopidogrel 75 mg qd Aspirin 75-100 mg qd 1,6, or 12 months VKA (target INR 2.0-3.0) Clopidogrel 75 mg qd Aspirin 75-100 mg qd XARELTO 15 mg qd* Clopidogrel 75 mg qd XARELTO 15mg QD Aspirin 75-100 mg qd VKA (target INR 2.0-3.0) Aspirin 75-100 mg qd End of treatment at 12 months Primary endpoint: TIMI major, minor, and bleeding requiring medical attention Secondary endpoint: CV death, MI, stroke, and stent thrombosis *10 mg od in patients with CrCl of 30 to <50 ml/min. Alternatively: 10 mg prasugrel od or 90 mg ticagrelor bid. Data on File. Janssen Pharmaceuticals, Inc. 31